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New group of brain malformations linked to protein-folding defects

neuronas cerebro plegamiento proteínas mutaciones share4rare
An international research team has identified a new category of genetic disorders caused by mutations affecting the TRiC/CCT folding complex.

The discovery of this new group of rare diseases, associated with brain malformations, intellectual disability, and seizures, was made possible by a unique medical case. A child in Germany had gone undiagnosed for a long time, despite suffering from intellectual disability, low muscle tone, and brain abnormalities. A genetic analysis finally revealed a mutation in the CCT3 gene, which encodes a subunit of the TRiC complex, responsible for properly folding proteins. With no prior evidence linking this mutation to any disease, researchers investigated it further.

Impact of the mutation: Studies in animal models

The research team first used the nematode C. elegans as a model organism, given that its CCT3 gene is equivalent to the human version. When they introduced the patient’s mutation into the worm, they observed that the affected protein did not function properly, leading to incorrect folding of actin—an essential protein for cellular structure. This resulted in nervous system development issues and impaired mobility in the worms. Similar findings were noted in other models: yeast cells exhibited cellular abnormalities, and zebrafish showed abnormal brain development. These results suggest that the mutation impacts neuromuscular function at various biological levels.

More cases of mutations in the TRiC complex

Following these studies, the team searched patient databases for cases of brain malformations and found 22 individuals with mutations in various subunits of the TRiC complex. All displayed similar neurological symptoms, confirming a connection between TRiC complex mutations, brain malformations, and neurological dysfunctions. The researchers proposed the term "TRiCopathies" for this new group of diseases linked to protein-folding defects.

Clinical implications and future research

This discovery highlights the critical role of protein folding in brain development. Identifying TRiCopathies helps provide a definitive diagnosis for cases that previously lacked clear identification, paving the way for research into targeted treatments. According to Stephen Pak, one of the study's authors, these findings could guide doctors and patients, enabling faster diagnoses when mutations in the TRiC complex are detected. The results have been published in the Science journal.

*SourceMutaciones que afectan al plegamiento de las proteínas como causa de malformaciones cerebrales

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